Method of production of 2-cyanoimino-1, 3-thiazolidine

ABSTRACT

A method for producing high purity 2-cyanoimino-1,3-thiazolidine comprising the steps of: 
     reacting an alkali metal cyanide compound, an alkali metal hydroxide, a lower alcohol and chlorine in an aqueous solution to form an carboimidic acid ester solution, then adding an organic solvent thereto, followed by adding a cyanamide solution to form an N-cyanocarbonimidic acid ester, and further extracting the resultant ester with an organic solvent extracting solution, followed by washing with an aqueous solution of a reducing agent solution to obtain a high purity, stable N-cyanocarbonimidic acid ester as a first step; and 
     reacting the N-cyanocarbonimidic acid ester obtained in the first step with 2-aminoethanethiol to be cyclicized as a second step to thereby obtain a 2-cyanoimino-1,3-thiazolidine.

TECHNICAL FIELD

The present invention relates to a method for industrially producing2-cyanoimino-1,3-thiazolidine useful as an intermediate material ofpharmaceuticals or agrochemicals. More specifically, it relates to amethod for producing a high purity 2-cyanoimino-1,3-thiazolidine using ahigh purity, stable intermediate N-cyanocarbonimidic acid ester, whichis obtained from an alkali metal cyanide compound, an alkali metalhydroxide, a lower alcohol, chlorine and cyanamide.

BACKGROUND ART

Several methods have been known for the production of anN-cyanocarbonimidic acid ester. For example, 1) European PatentPublication EP14,064 (A2) (1980), Japanese Unexamined Patent Publication(Kokai) No. 5-186412 (1993), and Japanese Unexamined Patent Publication(Kokai) No. 5-186413 (1993) propose a method for obtainingN-cyanocarbonimidic acid methyl ester from sodium hydroxide and methanoland gaseous state or liquid state chlorocyan/cyanogen chloride andcyanamide. This reaction is believed to be expressed by the followingformula:

Further, 2) German Patent Publication DE3,225,249 (A1) (1983) proposes amethod for obtaining N-cyanocarbonimidic acid methyl ester from sodiumcyanide, sodium hydroxide, methanol, chlorine and cyanamide as shown inthe following formula:

On the other hand, 3) as a method for producing2-cyanoimino-1,3-thiazolidine, the method of usingN-cyanocarbonimidodithioic acid ester is described in Arch. Pharm.(Weiheim, Ger.), 305 (10), P731 (1972), Japanese Unexamined PatentPublication (Kokai) No. 48-91064, Gazz. Chim. Ital., 110 (506), P345, WO92-17462 (1992), etc. This reaction is believed to be expressed by thefollowing formula:

Further, 4) as a method using similar starting materials, there is thedisclosure in Japanese Unexamined Patent Publication (Kokai) No.60-28969 (1985). This reaction is believed to be expressed by thefollowing formula:

Further, 5) regarding the method of using an N-cyanocarbonimidic acidester, J. Heterocycl. Chem., 24 (1), P275 (1987) describes a method ofusing a diphenyl ester. This reaction formula is as follows:

Further, 6) the method of using N-cyanocarbonimidic acid methyl ester isdescribed in Org. Prep. Proced. Int., 26 (6), P721 (1991), German PatentDE4427539 (A1) (1996), and European Patent EP695744 (A1) (1996). Thisreaction formula is as follows:

However, in the first proposal of using chlorocyan/cyanogen chloride, itis necessary to handle strongly poisonous chlorocyan/cyanogen chloridestarting material as a gas. Special care have to be taken over thematerial and air-tightness of the system and the treatment facilitiesfor the exhaust, drainage, etc., and therefore the use of this method onan industrial scale was difficult.

Further, also in the second proposal, a stable yield of the formedN-cyanocarbonimidic acid methyl ester could not be expected. Dependingon the situation, the yield sometimes extremely decreased. Quality-wiseas well, not only the purity is low, but also the stability becomespoor, and furthermore the hygroscopicity is strong and long term storageis not possible, and therefore it is difficult and uneconomical to usethis method on an industrial scale.

Further, many N-cyanocarbonimidic acid esters are high in solubility inorganic solvents. Accordingly, when concentrating and precipitating asolution containing the same to obtain crystals, the stability is poorand, therefore, the loss in the concentration stage is large and theyield becomes poor. Further, since due to the properties thereof, manyesters easily hydrolyze, care is required in the temperature at the timeof extraction or separation of liquid. Thus there has been a demand forsimply separating and drying the products so as to obtain stableproducts.

Further, in particular, when methylene chloride is used among theorganic solvents, since the boiling point of the methylene chloride islow, there are the problems that the yield is usually only about 50% andthe cost of the starting materials becomes high. To raise the yield,special equipment such as a coolant recirculating system becomesnecessary and therefore new capital investment is required.

On the other hand, in the third and fourth proposals using anothercompound, that is, N-cyanocarbonimidodithioic acid ester, as thestarting material for the 2-cyanoimino-1,3-thiazolidine, the toxicity orinflammability or odor of the gaseous methyl mercaptan dissociating atthe time of the reaction becomes a problem. Further, in the preparationof the compound, there is the problem that carbon disulfide having anextremely high inflammability or toxicity has to be used.

In the case of an N-cyanocarbonimidic acid ester, there are the effectsthat, since phenol or alcohol is produced as a byproduct, it is easilyto recover and recycle and simultaneously the problem of toxicity orodor is eliminated. In the fifth proposal, the diphenoxy compound usedis high in the price thereof and difficult to acquire. In the sixthproposal, the purity of the formed 2-cyanoimino-1,3-thiazolidine is lowand regardless of the method of production, inherently requiring carefulcontrol, the settings of the conditions were insufficient and anindustrially stable supply of products was difficult.

DISCLOSURE OF THE INVENTION

Accordingly, the object of the present invention is to solve the aboveproblems in the prior art and to develop a method for safelyindustrially producing, inexpensive N-cyanocarbonimidic acid ester and2-cyanoimino-1,3-thiazolidine.

Another object of the present invention is to provide a method forproducing an N-cyanocarbonimidic acid ester and2-cyanoimino-1,3-thiazolidine, as a high quality crystal, with a goodyield and high purity.

In accordance with the present invention, it is possible to produce ahigh purity, stable N-cyanocarbonimidic acid ester by reacting an alkalimetal cyanide compound, an alkali metal hydroxide, a lower alcohol andchlorine in an aqueous solution to form an carbonimidic acid estersolution, then adding an organic solvent thereto, followed by adding acyanamide solution to form an N-cyanocarbonimidic acid ester, andfurther extracting the resultant ester with an organic solventextracting solution, followed by washing with an aqueous solution of areducing agent.

In accordance with the present invention, it is possible to produce highpurity 2-cyanoimino-1,3-thiazolidine by reacting the high purity, stableN-cyanocarbonimidic acid ester obtained in the above method with2-aminoethanethiol to be cyclized, in particular, without complicatedpurification.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the relationship between the purity and themelting point of N-cyanocarbonimidic acid methyl ester.

MODE FOR CARRYING OUT THE INVENTION

Embodiments of the present invention will be explained in detail below.

According to the present invention, it is possible to produce theintended 2-cyanoimino-1,3-thiazolidine easily and safely, with the useof an alkali metal cyanide compound, an alkali metal hydroxide, a loweralcohol, chlorine and cyanamide to react with 2-aminoethanethiol throughan intermediate N-cyanocarbonimidic acid ester.

The first reaction of the present invention is considered to progress bythe following formula:

In the present invention, first, the alkali metal cyanide compound,alkali metal hydroxide, and lower alcohol are dissolved in water, thenchlorine gas is blown thereto to react and produce an carbonimidic acidester solution. In this reaction, the alkali metal hydroxide should beadded in an amount of preferably 0.5 to 3 equivalents, more preferably1.0 to 1.2 equivalents, to one mole of the alkali metal cyanidecompound. Further, in this reaction, a lower alcohol should be added inan amount of preferably about 2.0 to 5.0 equivalents, more preferably2.8 to 3.2 equivalents, to one mole of the alkali metal cyanidecompound. Further, in this reaction, chlorine should be added in anamount of preferably about 0.5 to 1.5 equivalents, more preferably 0.8to 1.2 equivalents, to one mole of an alkali metal cyanide compound.When the chlorine is insufficient, the yield is decreased. Even when anexcess amount of the chlorine is used, the intermediate tends to breakdown and become a dialkyl carbonic acid ester and the yield tends todecrease.

Specific examples of the alkali metal cyan compound are sodium cyanate,potassium cyanate, etc., but, from the viewpoint of economy andreactivity, the use of sodium cyanide is preferable.

Specific examples of the alkali metal hydroxide are sodium hydroxide,potassium hydroxide, etc., but, from the viewpoint of economy andreactivity, the use of sodium hydroxide is preferable.

Specific examples of the lower alcohol are methanol, ethanol, normalpropanol, isopropanol, etc., but the use of methanol is preferable fromthe viewpoint of economy and reactivity.

The temperature of this reaction may be suitably selected from theviewpoint of the suppression of decomposition of the starting materialsor imide carbonate ester formed and secondary reactions, but −5° C. to10° C. is most preferable. The reaction time is not particularlylimited, but is preferably 5 to 20 hours, more preferably 6 to 10 hours.

In the present invention, an organic solvent is added to thecarbonimidic acid ester solution, then cyanamide is added in an amountof preferably about 0.2 to 1.0 mole, more preferably 0.7 to 0.8 mole, toone mole of the alkali metal cyanide compound so as to produce ancarbonimidic acid ester solution. At this time, an acid is preferablyused to control the pH to 6.7 to 7.0.

The cyanamide used in this reaction can be added as a crystal orsolution. The solvent, when it is used as a solution, is notparticularly limited if the solvent can dissolve the starting materialsand does not react with the reaction starting materials and reactionintermediates, but water is preferably used in view of its low price andhigh safety. At that time, the concentration of cyanamide is preferablyabout 5 to 100% by weight, more preferably 10 to 60% by weight.

The reaction temperature of the reaction is not particularly limited,but the reaction can be preferably performed at 30° C., or less but 10to 25° C. is most preferable from the viewpoint of the reaction speed,the suppression of the decomposition of the starting materials orN-cyanocarbonimidic acid ester formed, etc. The time of addition of thecyanamide is not particularly limited, but preferably is 1 to 10minutes, more preferably 2 to 5 minutes. Further, as the aging time, thereaction should be completed in 1 to 5 hours and more preferably 2 to 3hours.

Specific examples of the acid for the control of the pH are hydrochloricacid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc.,but it is preferable to use hydrochloric acid or sulfuric acid from theviewpoint of economy.

After the reaction is completed, the oil layer is separated and isextracted one to five times using an equal weight or two times theweight of the organic solvent based upon the reaction solution.

Specific examples of the organic solvent for the extract of theN-cyanocarbonimidic acid ester are methylene chloride, chloroform,carbon tetrachloride, benzene, toluene, xylene, methyl acetate, ethylacetate, etc. From the viewpoint of stability considering thetemperature at the time of recovery or the economy considering thefacility for concentration and from the extraction efficiency, the useof chloroform is preferable. The extraction temperature is notparticularly limited, but it is possible to carry out the extraction ata temperature of 25° C. or less, and 0 to 15° C. is most preferable fromthe viewpoint of the extraction speed, the suppression of thedecomposition of the starting materials or the formed N-cyanimidecarbonate ester or secondary reactions, etc. The extraction time is notparticularly limited, but preferably is 30 minutes to 2 hours, morepreferably 30 minutes to 1 hour.

In the present invention, the extracted N-cyanimide carbonate ester isthen washed with an aqueous solution of a reducing agent and dehydrated.Due to this treatment, not only is it possible to ensure the stabilityof the N-cyanocarbonimidic acid ester in the manufacturing process, butalso it is possible to obtain a stable, high purity final product.

Specific examples of the reducing agent for the washing are sodiumhydrogensulfite, sodium sulfite, sodium thiosulfate, etc., but from theviewpoint of the economy considering the stability in an aqueoussolution or reducing ability, sodium hydrogensulfite or sodium sulfiteis desirable.

Further, the concentration and amount of the use of the aqueous solutionof the reducing agent for the washing is not particularly limited, butthe concentration of the aqueous solution of 1 to 50% by weight and theuse of {fraction (1/20)} to ½ of the weight of the extract arepreferable, but from the viewpoint of the volumetric efficiency, thesuppression of the load on the treatment of the wastewater, etc., thewashing is most preferably carried out at a concentration of the aqueoussolution of 2 to 10% by weight and using {fraction (1/10)} to ⅕ of theweight of the extract.

The temperature of this washing is not particularly limited, but thewashing is preferably suitably performed at a temperature of not morethan 25° C. From the viewpoint of the suppression of the decompositionof the materials or produced N-cyanocarbonimidic acid ester andsecondary reactions etc., 0 to 15° C. is most preferable. The extractiontime is not particularly limited, but is preferably 30 minutes to 2hours, more preferably 40 minutes to 1 hour.

On the other hand, Specific examples of the desiccant for thedehydration treatment are sodium sulfate, magnesium sulfate, calciumchloride, a molecular sieve, etc., but from the viewpoint of economyconsidering the efficiency of dehydration or solubility in the extract,the use of a molecular sieve is desirable. In particular, it is possibleto use Molecular Sieve (3A).

These extracts are concentrated in vacuo. After concentrated, theconcentrate is gradually cooled to a temperature of, for example, 5° C.or less to precipitate a crystal of N-cyanocarbonimidic acid ester. Theslurry is separated. The yield of the crystal thus obtained is usuallyat least 60% (based on alkali metal cyanide compound). The purity is atleast 99% (purity measured by HPLC method). Further, the rate ofproduction, including the filtrate, is at usually at least 90% (based onalkali metal cyanide compound).

The temperature for the concentration is not particularly limited, butthe concentration may be suitably carried out at 50° C. or less. The useof a temperature of 35 to 45° C. is most preferable from the viewpointof the extraction speed, suppression of the decomposition of thestarting materials or the formed N-cyanocarbonimidic acid ester andsecondary reactions, etc. The concentration time is not particularlylimited, but preferably is 30 minutes to 10 hours, more preferably 4hours to 7 hours.

Further, the filtrate after separation can be recycled as it is for theextraction of the next reaction.

It is essential that the above crystal is dried by completely removingthe organic solvent at the same time as the drying using a box typedrier, fluidized drier, flash drier, or other known drier, in particularwhen used for the next reaction. In particular, when used as a materialfor the below-mentioned 2-cyanoimino-1,3-thiazolidine, even if remainingin an amount on the order of several percent, sometimes no product isobtained at all.

The drying conditions differ depending on the drier, but when using abox type drier, from the viewpoint of the dehydration speed andprevention of decomposition of the N-cyanocarbonimidic acid esteranhydride, the solution is preferably dried at a drying temperature of10 to 80° C., more preferably 30 to 50° C., for preferably a drying timeof 30 minutes to 10 hours, more preferably 1 to 8 hours.

The second reaction of the present invention is believed to proceed asin the following formula:

In the present invention, a 2-aminoethanethiol mineral acid salt isadded to an alkali aqueous solution to react with theN-cyanocarbonimidic acid ester formed from the above reaction.

As the 2-aminoethanethiol salt, a hydrochloride, sulfate, nitrate,carbonate, acetate, etc. may be used, but from the reactivity, the useof a mineral acid salt is preferable. A hydrochloride is more preferablefrom the viewpoint of the solubility, economy, etc.

Further, as the alkali used for the neutralization, sodium hydroxide,potassium hydroxide, etc. may be used, but sodium hydroxide ispreferable from the viewpoint of economy and reactivity.

The preferable addition amount of alkali to the 2-aminoethanethiol saltis 1.9 to 2.1 equivalents per mole of the 2-aminoethanethiol salt, morepreferably 1.95 to 2.05 equivalents.

Further, instead of a 2-aminoethanethiol, it is possible to use the freecompound for the reaction. In this case, it is also possible to use thesame in the form of a solution. The preferable amount of alkali added tothe 2-aminoethanethiol is 0.9 to 1.1 equivalents per mole of the2-aminoethanethiol salt, more preferably 0.95 to 1.05 equivalents.

The 2-aminoethanethiol solution used was obtained by using the samesolvent as the reaction solvent or a solvent miscible with the reactionsolvent and adjusted to a concentration of 20 to 30% by weight.

The reaction temperature, when adding an N-cyanocarbonimidic acid ester,is preferably 20° C. or less from the viewpoint of prevention ofdecomposition of the N-cyanocarbonimidic acid ester solution. Ifconsidering the reaction speed, 0C to 10° C. is further preferred. Thepreferable reaction time is 20 minutes to 3 hours.

In the present invention, the pH of the above reaction solution isadjusted with an acid, then heated to carry out a desired cyclizationreaction to obtain a crystal of the intended2-cyanoimino-1,3-thiazolidine. This cyclization reaction is preferablycarried out at a pH of 10 to 11, more preferably a pH of 10.2 to 10.6.

The acid usable for the adjustment of pH is not particularly limited,but mineral acids such as hydrochloric acid, sulfuric acid, nitric acidmay be exemplified. The use of various types of solvents is alsopossible, but the use of hydrochloric acid is preferable from theviewpoint of the reactivity, easy availability, having, etc. Thisreaction is carried out by adding an acid of a concentration of, forexample, 5 to 100% by weight at a speed maintaining a reactiontemperature of 10 to 30° C., more preferably a reaction temperature of15 to 25° C.

The reaction temperature of the cyclization reaction is preferably atemperature of 45° C. or less from the viewpoint of prevention ofpolymerization and other secondary reactions. Considering the reactionspeed, a temperature of 35 to 40° C. is further preferable. The reactiontime is not particularly limited, but is preferably 5 to 15 hours, morepreferably 7 to 10 hours.

After the end of the reaction, the reaction solution is gradually cooledto, for example, a temperature of 15° C. or less and adjusted in pH,then the crystal of 2-cyanoimino-1,3-thiazolidine is precipitated. ThepH is adjusted to preferably a pH of 5.5 to 7.5, more preferably a pH of6.6 to 7.0. The acid usable for adjusting the pH is not particularlylimited. For example, mineral acids such as hydrochloric acid, sulfuricacid, nitric acid, may be exemplified. Various solutions may be used,but the use of hydrochloric acid is preferably from the viewpoint of thereactivity or easy availability. This slurry solution is cooled to atemperature of, for example, 15° C. or less, then the slurry isseparated. The yield of the crystal of 2-cyanoimino-1,3-thiazolidinethus obtained is usually at least 80% (based on cyanamide) and thepurity at least 99% (measured by HPLC).

The drying conditions differ depending on the drier, but when using abox type drier, from the viewpoint of the prevention of decomposition ofthe 2-cyanoimino-1,3-thiazolidine, the solution is preferably dried at adrying temperature of 60 to 80° C., more preferably 65 to 75° C., forpreferably a drying time of 30 minutes to 48 hours, more preferably 8 to16 hours.

EXAMPLES

The present invention will be explained in more detail by the followingExamples, but the present invention is, of course, not limited to theseExamples.

Example 1

A 1000 ml four-necked flask provided with a thermometer and stirringdevice was charged with 108 g (6.0 moles) of water. While stirring,256.0 g (1.6 moles) of a 25% by weight aqueous solution of sodiumhydroxide and 70.9 g (1.5 moles) of sodium cyanide were added. Whilemaintaining the temperature at 5° C. or less, chlorine gas (1.5 moles)was reacted over 6 hours. After the end of the reaction, the residualchlorine gas was exhausted outside of the system by nitrogen gas. Next,while maintaining the temperature of 5° C. or less, a 36% by weightaqueous solution of hydrochloric acid was added, the pH was adjusted to7.0, then 350 ml (2.0 moles) of chloroform was added.

142.0 g (0.85 mole) of a 25% by weight aqueous solution of cyanamide wasadded and a 36% by weight aqueous solution of hydrochloric acid wasgradually added, whereby a reaction was carried out for 2 hours, whileadjusting the pH to 6.6 to 7.0. Next, the aqueous layer was extractedtwo times with 300 ml (1.7 moles) of chloroform.

The chloroform solution thus obtained was rinsed twice with 200 g (0.07mole) of a 5% by weight aqueous solution of sodium hydrogensulfite, thendehydrated with 5.0 g of Molecular Sieve 3A. The molecular sieve wasfiltered out, then the solution was concentrated in vacuo, whereby awhite crystal was obtained. This was filtered by suction filtration toobtain 63.1 g of wet crystal of N-cyanocarbonimidic acid methyl ester.The resultant crystal was dried in vacuo at 40° C. for 5 hours to obtain62.1 g of N-cyanocarbonimidic acid methyl ester having a purity of 99.7%(yield 63.5%=converted value of purity from cyanamide (Note: the samebelow)). The melting point of the N-cyanocarbonimidic acid methyl esterthus obtained was 61° C. The relationship between the purity and themelting point is shown in FIG. 1. Then, the changes in purity of theN-cyanocarbonimidic acid methyl ester over time were tested by thefollowing method.

That is, a 50 ml sample flask was charged with 10 g ofN-cyanocarbonimidic acid methyl ester having a purity of 99.7%, sealed,then stored in a 25° C. thermostat. After about 3 months, the flask wastaken out and the purity analyzed. The results are shown in Table I.

Note that the filtrate the obtained weighed 65.4 g. The concentration ofthe N-cyanocarbonimidic acid methyl ester in the solution was 30.4%. Thevalue corresponds to 20.0% converted to yield.

A 300 ml four-necked flask provided with a thermometer and stirringdevice was charged with 100 ml (2.9 moles) of water. While stirring,83.2 g (0.5 mole) of a 25% by weight aqueous solution of sodiumhydroxide was added, then 28.6 g (0.25 mole) of 2-aminoethanethiolhydrochloride was added and the solution heated and dissolved at 30° C.Next, while maintaining the temperature at 5° C. or less, 28.6 g (0.25mole) of the N-cyanocarbonimidic acid methyl ester was added and areaction is carried out for 2 hours. Next, the solution was warmed to20° C., the pH was adjusted to 10.5 with a 36% by weight aqueoussolution of hydrochloric acid, then a reaction was carried out at 40° C.for 8 hours.

After the end of the reaction, the solution was cooled to a temperatureof 10° C., the pH was adjusted to 4.5 with a 36% by weight aqueoussolution of hydrochloric acid, then the solution was filtered by suctionfiltration to obtain 38.9 g of 2-cyanoimino-1,3-thiazolidine. This wasdried in vacuo at 70° C. for 8 hours to obtain2-cyanoimino-1,3-thiazolidine having a purity of 99.7% at a yield of88.0% (based on charged methyl N-cyanoimide carbonate).

Example 2

A reaction and extraction were carried out in the same way as in Example1, then the filtrate of Example 1 was mixed in the extract and themixture was similarly concentrated, precipitated, and dried to obtain78.2 g of N-cyanocarbonimidic acid methyl ester having a purity of99.9%. The yield from the cyanamide was 80.7%. The melting point of theN-cyanocarbonimidic acid methyl ester thus obtained was 61° C. Therelationship between the purity and the melting point is shown in FIG.1. Next, the changes in purity are shown in Table I.

Note that the filtrate obtained in Example 2 weighed 71.5 g. Theconcentration of the N-cyanocarbonimidic acid methyl ester in thesolution was 29.8%. The value corresponds to 25.3% converted to yield.

A 300 ml four-necked flask provided with a thermometer and stirringdevice was charged with 100 ml (2.9 moles) of water. While stirring,83.2 g (0.5 mole) of a 25% by weight aqueous solution of sodiumhydroxide was added, then 28.6 g (0.25 mole) of 2-aminoethanethiolhydrochloride was added and the solution heated and dissolved to 30° C.Next, while maintaining the temperature at 5° C. or less, 28.6 g (0.25mole) of the N-cyanocarbonimidic acid methyl ester was added and areaction is carried out for 2 hours. Next, the solution was warmed to20° C., the pH was adjusted to 10.5 with a 36% by weight aqueoussolution of hydrochloric acid, then a reaction was carried out at 40° C.for 8 hours.

After the end of the reaction, the solution was cooled to a temperatureof 10° C., the pH was adjusted to 4.5 with a 36% by weight aqueoussolution of hydrochloric acid, then the solution was filtered by suctionfiltration to obtain 38.9 g of 2-cyanoimino-1,3-thiazolidine. This wasdried in vacuo at 70° C. for 8 hours to obtain2-cyanoimino-1,3-thiazolidine having a purity of 99.7% at a yield of88.0% (based on charged N-cyanocarbonimidic acid methyl ester).

Comparative Example 1

A 1000 ml four-necked flask provided with a thermometer and stirringdevice was charged with 108 g (6.0 moles) of water. While stirring,240.0 g (1.5 moles) of a 25% by weight aqueous solution of sodiumhydroxide and 68.6 g (1.4 moles) of sodium cyanide were added. Whilemaintaining the temperature at 5° C. or less, chlorine gas (1.5 moles)was reacted over 6 hours. After the end of the reaction, the residualchlorine gas was exhausted outside of the system with nitrogen gas.Next, the pH was adjusted to 7.0 with a 36% by weight aqueous solutionof hydrochloric acid, then 350 ml (2.0 moles) of chloroform was added.

155.0 g (1.0 mole) of a 27% by weight aqueous solution of cyanamide and53.7 g (0.53 mole) of a 36% by weight aqueous solution of hydrochloricacid were added (the pH at that time being 6.6) and a reaction wascarried out for 2 hours, then this was separated and the aqueous layerwas extracted two times with 300 ml (1.7 moles) of chloroform. Theobtained chloroform solution thus obtained was concentrated in vacuo andcooled to obtain a white crystal. This was filtered by suctionfiltration to obtain 38.8 g of wet crystal of N-cyanocarbonimidic acidmethyl ester. This was dried in vacuo at 40DC for 5 hours to obtain 34.8g of N-cyanocarbonimidic acid methyl ester having a purity of 92.8%(yield 28.3%). The melting point of the N-cyanocarbonimidic acid methylester thus obtained was 58° C. The relationship between the purity andthe melting point is shown in FIG. 1. Next, the changes in purity areshown in Table I.

A 300 ml four-necked flask provided with a thermometer and stirringdevice was charged with 100 ml (2.9 moles) of water. While stirring,83.2 g (0.5 mole) of a 25% by weight aqueous solution of sodiumhydroxide was added, then 28.6 g (0.25 mole) of 2-aminoethanethiolhydrochloride was added and the solution was heated and dissolved at 30°C. Next, while maintaining the temperature at 5° C. or less, 20.5 g(0.18 mole) of the N-cyanocarbonimidic acid methyl ester was added and areaction was carried out for 2 hours. Next, the solution was warmed to20° C., the pH was adjusted to 9.5 with a 36% by weight aqueous solutionof hydrochloric acid, then a reaction was carried out at 40° C. for 8hours, but polymerization occurred in 2 hours of time and the reactionended in failure.

Comparative Example 2

A 1000 ml four-necked flask provided with a thermometer and stirringdevice was charged with 108 g (6.0 moles) of water. While stirring,256.0 g (1.6 moles) of a 25% by weight aqueous solution of sodiumhydroxide and 70.9 g (1.5 moles) of sodium cyanide were added. Whilemaintaining the temperature at 5° C. or less, chlorine gas (1.5 moles)was reacted over 6 hours. After the end of the reaction, the residualchlorine gas was exhausted outside of the system by nitrogen gas. Then,while holding maintaining the temperature at 5° C. or less, a 36% byweight aqueous solution of hydrochloric acid was added, the pH wasadjusted to 7.0, then 350 ml (2.0 moles) of chloroform was added.

142.0 g (0.85 mole) of a 25% by weight aqueous solution of cyanamide wasadded and a reaction was carried out for 2 hours while adjusting the pHto 6.6 to 7.0 with a 36% by weight aqueous solution of hydrochloricacid, then separated and the aqueous layer was extracted two times with300 ml (1.7 moles) of chloroform. The chloroform solution thus obtainedwas dehydrated with 5.0 g of Molecular Sieve 3A. The solution wasfiltered by the molecular sieve, then concentrated in vacuo and cooledto obtain a white crystal. This was filtered by suction filtration toobtain 77.1 g of wet crystal of methyl N-cyanocarbonimidic acid methylester. This was dried in vacuo at 40° C. for 5 hours to obtain 71.8 g ofN-cyanocarbonimidic acid methyl ester having a purity of 94.0% (yield69.7%). The yield from the cyanamide was 80.7%. The melting point of theN-cyanocarbonimidic acid methyl ester thus obtained was 56.9° C. Therelationship between the purity and the melting point is shown in FIG.1. Next, the changes in purity are shown in Table I.

A 300 ml four-necked flask provided with a thermometer and stirringdevice was charged with 100 ml (2.9 moles) of water. While stirring,83.2 g (0.5 mole) of a 25% by weight aqueous solution of sodiumhydroxide was added, then 28.6 g (0.25 mole) of 2-aminoethanethiolhydrochloride was added and the solution heated and dissolved at 30° C.Then, while maintaining the temperature at 5° C. or less, 30.4 g (0.25mole) of the N-cyanocarbonimidic acid methyl ester was added and areaction was carried out for 2 hours. Next, the solution was warmed to20° C., the pH was adjusted to 9.5 with a 36% by weight aqueous solutionof hydrochloric acid, then the solution was warmed to 40° C., the pH wasadjusted to 9.0 with or 36% by weight aqueous solution of hydrochloricacid, a reaction was carried out for 8 hours.

After the end of the reaction, the solution was cooled to a temperatureof 10° C., the pH was adjusted to 6.0 with a 36% by weight aqueoussolution of hydrochloric acid, then the solution was filtered by suctionfiltration to obtain 35.4 g of 2-cyanoimino-1,3-thiazolidine. This wasdried in vacuo at 70° C. for 8 hours to obtain 25.1 g having a purity of90.3% (at a yield of 70.5%, based on the charged N-cyanocarbonimidicacid methyl ester).

TABLE I Change of Purity of N-cyanocarbonimidic Acid Methyl Ester AlongWith Time No. of days elapsed (days) 0 180 Remarks Purity of N- 99.798.9 Ex. 1 cyanocarbonimidic 99.9 98.1 Ex. 2 acid methyl ester 92.8 88.8Comp. Ex. 1 (%) 94.0 91.0 Comp. Ex. 2

Industrial Applicability

According to the method of the present invention, in the practice of2-cyanoimino-1,3-thiazolidine on an industrial scale, it is possible tosolve the various problems of the conventional methods, that is, thehazard of the by-products, the higher cost of the manufacturingfacilities etc. accompanying this, and the insufficient yield andproduce the desired compound, that is, 2-cyanoimino-1,3-thiazolidine, onan industrial scale with the use of a high purity N-cyanocarbonimidicacid ester.

What is claimed is:
 1. A method for producing high purity2-cyanoimino-1,3-thiazolidine comprising the steps of: reacting analkali metal cyanide compound, an alkali metal hydroxide, a loweralcohol and chlorine in an aqueous solution to form an carboimidic acidester solution, then adding an organic solvent thereto, followed byadding a cyanamide solution to form an N-cyanocarbonimidic acid ester,and further extracting the resultant ester with an organic solventextracting solution, followed by washing with an aqueous solution of areducing agent, whereby a high purity, stable N-cyanocarbonimidic acidester is obtained as a first step; and reacting the N-cyanocarbonimidicacid ester obtained in the first step with 2-aminoethanethiol to becyclicized as a second step to thereby obtain a2-cyanoimino-1,3-thiazolidine.
 2. A method of production as claimed inclaim 1, wherein a molar ratio of the alkali metal cyanide compound andthe cyanamide is 1:1 to 0.2.
 3. A method of production as claimed inclaim 1, wherein the cyanamide is reacted, while controlling the pH ofthe carboimidic acid ester solution to 6.7 to 7.0.
 4. A method ofproduction as claimed in claim 1, wherein the organic solvent ischloroform.
 5. A method of production as claimed in claim 1, wherein thereducing agent is at least one reducing agent selected from the groupconsisting of sodium hydrogensulfite, sodium sulfite, and sodiumthiosulfate.
 6. A method for producing an N-cyanocarbonimidic acid estercomprising the steps of: reacting an alkali metal cyanide compound, analkali metal hydroxide, a lower alcohol and chlorine in an aqueoussolution to form an carboimidic acid ester solution; then adding anorganic solvent thereto, followed by adding a cyanamide solution toforms an N-cyanocarbonimidic acid ester; and further extracting theresultant ester with an organic solvent extracting solution, followed bywashing with an aqueous solution of a reducing agent.
 7. A method ofproduction as claimed in claim 6, wherein a mother liquor afterproducing the N-cyanocarbonimidic acid ester is mixed and recycled tothe extracting solution for the N-cyanocarbonimidic acid ester.
 8. Amethod of production as claimed in claim 1, wherein the purity of thewashed high purity, stable N-cyanocarbonimidic acid ester is at least99%.
 9. A method of production as claimed in claim 6, wherein the purityof the washed high purity, stable N-cyanocarbonimidic acid ester is atleast 99%.